Enhanced therapeutic potential of [177Lu]Lu-DOTAGA.Glu.(FAPi)2 and [177Lu]Lu-DO3A.Glu.(FAPi)2 in targeting FAP-positive tumors

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Ziel/Aim: The present study aims at evaluating the in vitro and in vivo performance of two lutetium-177 labeled FAP-based dimers, DOTAGA.Glu . (FAPi) 2 and DO3A.Glu.(FAPi) 2 , to investigate their potential to serve as therapeutic tools for FAP-expressing tumors. Methodik/Methods: DOTAGA.Glu . (FAPi) 2 and DO3A.Glu . (FAPi) 2 were labeled with lutetium-177. Both dimers were evaluated in vitro (lipophilicity, protein binding, saturation, internalization and externalization) on immortalized CAFs. In vivo studies (biodistribution, metabolic stability, protein binding, SPECT/CT and autoradiography) were performed on PC3 xenografts. Ergebnisse/Results: [ 177 Lu]Lu-DOTAGA.Glu . (FAPi) 2 and [ 177 Lu]Lu-DO3A.Glu . (FAPi) 2 were prepared with molar activities between 6 to 30 MBq/nmol and their logD octanol/PBS values were found to be -3±0.1 and -1.7±0.01 respectively. Both 177 Lu-labeled tracers exhibited high affinity for FAP, with Kd values of 0.7 in both cases, and high internalization rate reaching a maximum of about 35% in relation to the total cell bound activity already after 30 min of incubation with the CAFs. Metabolic studies performed after 30 min and 60 min p.i., revealed that both tracers are stable in vivo. In vivo protein binding showed that [ 177 Lu]Lu-DOTAGA.Glu . (FAPi) 2 and [ 177 Lu]Lu-DO3A.Glu . (FAPi) 2 bind to the protein in 79% and 75% after 30 min p.i., increasing to 86% and 92% after 60 min p.i., respectively. Biodistribution studies of [ 177 Lu]Lu-DOTAGA.Glu . (FAPi) 2 and [ 177 Lu]Lu-DO3A.Glu . (FAPi) 2 showed that the tumor uptake was 16.2±2.5 and 15±1.2% IA/g at 4 h p.i., respectively. Tumor uptake slowly decreased over time, reaching 5.1±0.1 and 2.8±0.4%IA/g at 48 h, respectively. Both tracers exhibited low blood retention level, decreasing from around 2.0±0.1% IA/g at 4 h p.i to 0.2±0.1 and 0.03±0.01% IA/g at 48 and 96 h p.i. Both tracers demonstrated high tumor-to-background ratios at all tested time points. These findings are well illustrated by SPECT/CT imaging. In vivo autoradiography confirmed the heterogeneous distribution of FAP receptors within PC3 xenografted tumors. Schlussfolgerungen/Conclusions: The results provide strong evidence for the potential use of 177 Lu]Lu-DOTAGA.Glu . (FAPi) 2 and [ 177 Lu]Lu-DO3A.Glu . (FAPi) 2 as therapeutic radiotracers for targeting FAP-expressing tumors. Publication History Article published online: 12 March 2025 © 2025. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany

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